Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans.
Oncotarget
; 6(5): 3420-31, 2015 Feb 20.
Article
em En
| MEDLINE
| ID: mdl-25638164
ABSTRACT
Somatic hypermethylation of the O6-methylguanine-DNA methyltransferase gene (MGMT) was previously associated with G > A transition mutations in KRAS and TP53 in colorectal cancer (CRC). We tested the association of MGMT methylation with G > A mutations in KRAS and TP53 in 261 CRCs. Sixteen cases, with and without MGMT hypermethylation, were further analyzed by exome sequencing. No significant association of MGMT methylation with G > A mutations in KRAS, TP53 or in the whole exome was found (p > 0.5 in all comparisons). The result was validated by in silico comparison with 302 CRCs from The Cancer Genome Atlas (TCGA) consortium dataset. Transcriptional silencing associated with hypermethylation and stratified into monoallelic and biallelic. We also found a significant clustering (p = 0.001) of aberrant hypermethylation of MGMT and the matrix metalloproteinase gene ADAMTS14 in normal colonic mucosa of CRC patients. This suggested the existence of an epigenetic field defect for cancerization disrupting the methylation patterns of several loci, including MGMT or ADAMTS14, that may lead to predictive biomarkers for CRC. Methylation of these loci in normal mucosa was more frequent in elder (p = 0.001) patients, and particularly in African Americans (p = 1 × 10-5), thus providing a possible mechanistic link between somatic epigenetic alterations and CRC racial disparities in North America.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Negro ou Afro-Americano
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Neoplasias Colorretais
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Metilases de Modificação do DNA
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Adenocarcinoma
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Colo
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Metilação de DNA
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Proteínas Supressoras de Tumor
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Enzimas Reparadoras do DNA
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Proteínas ADAM
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Mucosa Intestinal
Tipo de estudo:
Etiology_studies
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Observational_studies
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Prognostic_studies
Limite:
Humans
País como assunto:
America do norte
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article